N-Heterocyclic carbene-catalyzed deaminative cross-coupling of aldehydes with Katritzky pyridinium salts

Article abstract of DOI:10.1039/d0sc00225a

By employing an N-heterocyclic carbene (NHC) catalyst, we developed a versatile catalytic system that enables deaminative cross-coupling reactions of aldehydes with redox-active pyridinium salts. Katritzky pyridinium salts behave as single-electron oxidants capable of generating alkyl radicals enabled by the redox properties of the enolate form of Breslow intermediates. The resultant alkyl radical undergoes efficient recombination with the NHC-bound aldehyde-derived carbonyl carbon radical for the formation of a C-C bond. The mild and transition metal-free reaction conditions tolerate a broad range of functional groups, and its utility has been further demonstrated by the modification of a series of peptide feedstocks and application to the three-component dicarbofunctionalization of olefins.

Full text of DOI:10.1039/d0sc00225a

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N-Heterocyclic Carbene-Catalyzed Deaminative Cross-Coupling of
Aldehydes with Katritzky Pyridinium Salts
Inwon Kim,ab Honggu Im,ab Hyeonyeong Lee,ab and Sungwoo Hong*ba
Received 00th January 20xx,
Accepted 00th January 20xx
By employing an N-heterocyclic carbene (NHC) catalyst, we developed a versatile catalytic system that enables deaminative
cross-coupling reactions of aldehydes with redox-active pyridinium salts. The Katritzky pyridinium salts behave as single-
electron oxidants capable of generating alkyl radicals enabled by the redox properties of the enolates form of Breslow
intermediates. The resultant alkyl radical undergoes efficient recombination with the NHC-bound aldehyde-derived carbonyl
carbon radical for the formation of the C–C bond. The mild and transition metal-free reaction conditions tolerate a broad
range of functional groups, and its utility has been further demonstrated by the modification of a series of peptide feedstocks
and application to the three-component dicarbofunctionalization of olefins.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
redox-active esters such as N-(acyloxy)phthalimides, which
demonstrated that merging NHC catalysis and single-electron
chemistry has significant potential to forge C–C bonds.17 Despite the
significant advances in NHC-enabled radical reactions, single-
electron oxidants that are suitable for effective cross-coupling remain
limited. In this context, there is a growing demand for the
identification of new types of SET oxidants that enable cross-coupling
reactions with NHC-bound aldehyde-derived carbonyl carbon
radicals in a predictable and controllable manner.
Utilization of widely available and naturally abundant functionalities
is of great interest because it promises a convenient and cost-effective
synthetic method to enable the rapid modification of an important
class of feedstocks. α-Amino acids and their derivatives are prevalent
structural motifs across natural products1 and medicinally relevant
compounds,2 and the development of a general method to exploit them
as synthetic intermediates is highly desirable for rapid modification
and generating new chemical entities with broad utility. Recently,
Katritzky pyridinium salts, easily prepared from the condensation of
primary amines with commercially available pyrylium salts, have
emerged as a powerful tool for the generation of alkyl radical species.3
Watson,4 Glorius,5 Aggarwal,6 Shi,7 Gryko,8 Xiao,9 Martin,10
Rueping,11 and Molander12 have demonstrated the utility of the
Katritzky salts to forge various types of C–C and C–B bonds via
deaminative cross-coupling under Ni-catalyzed or photomediated
conditions (Scheme 1a). Despite the impressive achievements in this
field, a synthetic method that efficiently transforms an amine
functionality into a carbonyl group via deaminative radical pathway
is still underexplored.
In recent years, NHC-catalyzed radical reactions have shown great
potential as a new aspect of reactivity in contrast to what is typically
seen as an organocatalyst for the umpolung of aldehydes.13 The
Fukuzumi group observed a single electron transfer (SET) from the
enolate form of Breslow intermediates.14 The Studer group disclosed
the esterification of aldehydes via NHC catalysis using TEMPO in
single-electron oxidation.15 Since these pioneering works, important
contributions in the arena of NHC-catalyzed SET reactions have been
achieved.16 Very recently, the Ohmiya group reported
decarboxylative radical couplings of Breslow intermediates with
a.Department of Chemistry, Korea Advanced Institute of Science and Technology
(KAIST), Daejeon, 34141, Korea.
b.Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science
(IBS), Daejeon 34141, Korea.
Electronic Supplementary Information (ESI) available: Experimental procedure,
characterization of new compounds (1H and 13C NMR spectra).
Scheme 1 Design Plan: NHC-Catalyzed Deaminative Coupling of
Aldehydes with Katritzky Salts.
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Inspired by the aforementioned studies on NHC-catalyzed SET
reactions, we questioned whether redox-active amines such as
Katritzky salts could be directly reduced by the enolate form of the
Breslow intermediate. As outlined in Scheme 1c, we imagined that the
alkyl radical generated by the SET pathway could be combined with
the reduced enolate form of the Breslow intermediate, which would
present a new opportunity for the rapid modification of a series of
amino acid-derived and peptidic compounds. This powerful
transformation offers a new retrosynthetic disconnection via C−N
bond cleavage for the synthesis of high-value carbonyl compounds.
Room temperature is sufficient for these cross-coupling reactions, and
the photomediated process is not required. Moreover, challenging
intermolecular three-component dicarbofunctionalization of alkenes
can be successfully achieved through a radical relay with complete
regioselectivity.
4
5
toluene instead of DMSO
THF instead of DMSO
water instead of DMSO
Without NHC catalyst
NHC2 insteade of NHC1
NHC3 insteade of NHC1
in dark
28
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DOI: 10.1039/D0SC00225A
22
6
17
0
7
8c
9
21
42
10
11
72
with TEMPO
trace
a Reaction conditions: 1a (0.1 mmol), 2a (1.5 equiv), NHC (20 mol%) and Cs2CO3
(0.5 equiv) in solvent (1.0 mL) at rt for 15 h under N2. b Yields were determined by
1H NMR spectroscopy.
To examine the versatility and generality of the current
methodology, the optimized conditions were then applied to various
Katritzky salts derived from natural and unnatural amino acid
precursors, as summarized in Table 2. In general, about 10-20% of the
Katritzky salts 1 remained unreacted, and deamination products
(~10%) were observed as major by-products generated from hydrogen
atom abstraction (see the Scheme S1 for details). Exploration
demonstrated that a series of substrates bearing electron-rich or
electron-deficient groups such as aliphatic, phenyl, thiomethyl, and
ester groups, reacted readily under the optimized conditions to afford
the desired cross-coupled products 3a-3h. Pyridinium salts derived
from phenylalanine and homophenylalanine also readily participated
in the reaction to deliver the corresponding products 3g and 3h,
respectively. The method was suitable with chloro-substituents to
provide the corresponding product 3i, thus enabling further
derivatization. The Katritzky salts containing a phenolic group
(tyrosine) and an indole group (tryptophan) were also well tolerated
to produce ketone products 3j and 3o, respectively. Leucine
derivatives bearing a methyl ester group and a 2-naphthyl amide group
could be employed in this transformation to afford the desired
products 3l and 3m. The structure of 3m was unambiguously
confirmed by X-ray crystallographic analysis.18 The Cbz-protected
amine group was intact under the standard conditions to provide the
desired product 3n, thus enabling post-transformation. An allyl group
was compatible in this reaction and produced the corresponding
product 3k. Moreover, the current method can also be extended to
Katritzky salts derived from non-amino acids such as 4-amino-1-Boc-
piperidine, 4-aminotetrahydropyran, and 2-aminoindane to afford the
desired products 3p, 3q, and 3r, respectively. In addition, the current
method was suitable for the late-stage modification of biologically
relevant molecules such as DOPA and Tamiflu derivatives (3s and 3t).
Peptides are one of the most important classes of biomolecules and
have gained attention as therapeutic agents.19 In this context, site-
selective late-stage modification of peptides holds vast potential for
chemical biology and drug discovery by expanding the druggable
target space. Various Katritzky salts derived from dipeptides were
investigated under the optimal reaction conditions. To our delight, the
strategy was successfully applied to dipeptides as exemplified by 3u
(Phe-Ala), 3v (Phe-Phe), 3w (Met-Gly) and 3x (Leu-Gly). The
structure of 3y from the Ala-Phe peptide was assigned by X-ray
crystallographic analysis.18 Importantly, the excellent performance
was further demonstrated by the tolerance of the more complex setting
of peptides, such as tri- and tetrapeptides (3z-3ad).
Results and discussion
To test the viability of this scenario, our investigation was initiated by
monitoring the reactivity of Katritzky salt 1a derived from glutamic
acid with aldehyde 2a, and the results are enumerated in Table 1. After
screening the reaction parameters, we were pleased to find that the
desired transformation was feasible to afford the coupling product 3a
in 74% yield in the presence of a catalytic amount of the seven-
membered ring fused thiazolium salt NHC1 and Cs2CO3 in DMSO at
room temperature. Among the solvents screened, DMSO was optimal,
and less polar solvents led to significantly lower yields (entries 2-5).
A thorough survey of NHC catalysts revealed that the N-substituent
and backbone of the NHC precursors were critical in this reaction:
NHC precursors bearing an N-mesityl group (NHC2) or a cyclohexyl
group as the backbone (NHC3) furnished lower yields (entries 8 and
9). The choice of base was critical for the reaction efficiency and
screening of various bases indicated that Cs2CO3 was most effective.
As expected, control experiments verified that the NHC catalyst was
indispensable for the successful reaction (entry 7). Comparable
reactivity was observed when the reaction occurred in dark conditions,
revealing that visible light is not required for this transformation
(entry 10). We found that the reaction was completely inhibited in the
presence of TEMPO, suggesting that a radical pathway is likely to be
operative (entry 11).
Table 1 Optimization of NHC-Catalyzed Deaminative Alkylation of
Aldehydea
Entry
Variation from the standard conditions
Yield (%)b
1
2
3
none
74
36
42
We subsequently evaluated the scope of aldehydes to extend the
generality of this methodology. A series of aldehyde substrates
bearing both electron-donating and electron-withdrawing groups on
the aryl rings, such as methyl, methylthio, methoxy, cyano, ester,
MeCN instead of DMSO
1,2-DCE instead of DMSO
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Table 2 Scope of Amine and Aldehyde Substratesa
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DOI: 10.1039/D0SC00225A
a Reactions were performed by using 1 (0.15 mmol), 2 (1.5 equiv), NHC1 (20 mol%), Cs2CO3 (0.5 equiv) in solvent (1.0 mL) at rt under N2 for 16-24 h. Yields of
isolated products. b 50 oC.
Table 3 Substrate scope of Three-Component Reactiona
a Reactions were performed by using 1 (0.15 mmol), 2 (1.5 equiv), NHC1 (20 mol%), Cs2CO3 (0.5 equiv) and DMSO/MeCN (1:1) at rt under N2 for 16-24 h. Yields
of isolated products (dr 1:1).
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trifluoro, and trifluoromethoxy groups, worked well under the
To elucidate the reaction pathway, we conducted several control
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DOI: 10.1039/D0SC00225A
experiments (Scheme 2). First, we observed that reactions with a
optimized conditions (3ae-3ak), as shown in Table 2.
The reaction was compatible with fluoro, chloro, and bromo Katritzky salt bearing an internal alkene, producing cyclized lactone
substituents, thus offering an opportunity for the formation of further compound 7 along with the directly coupled product 8 (Scheme 2a).
C–C or C–heteroatom bonds (3al-3an). Meta- and ortho-substituents Next, when TEMPO was added in the standard conditions for radical-
were tolerated in the standard conditions (3ao-3ar). In addition, a trapping experiments, a considerable amount of alkyl and ketyl
vanillin derivative was successfully transformed to provide the radical-trapped TEMPO adducts 9 and 10 were isolated. Under the
desired product 3as. The scope of the reaction was further extended conditions, the deaminative cross-coupled product 3g was not
to other various (hetero)arenes such as naphthalene, thiophene, detected by crude HRMS and NMR (Scheme 2b). These two control
benzofuran, pyridine, and coumarin, to yield the corresponding experiments demonstrated that alkyl radicals from the deaminative
products 3at-3ax.
process and carbonyl-carbon radicals are present in this reaction
To further highlight the broad applicability of the reaction, we system. In addition, we used the cyclic voltammetry to measure the
questioned whether the current NHC catalysis enables the vicinal pyridinium salt 1a, and the reduction potential of 1a was −0.60 V vs.
alkyl carbofunctionalization of alkenes through a radical relay SCE (see the SI), indicating that the enolate form of the Breslow
mechanism involving a SET from the enolate form and radical intermediate (E0 = –0.97 V vs. SCE)14 may attain sufficient
ox
addition of the resultant alkyl radical to an alkene followed by reduction potential for Katritzky salts.
radical−radical coupling. Remarkably, the synthetic utility was further
magnified by the three-component dicarbofunctionalization of olefins
when alkenes were employed as coupling reagents. As highlighted in
Table 3, a range of pyridinium salts were successfully reacted with 2-
vinyl naphthalene under slightly modified reaction conditions in
which DMSO and MeCN were used as the cosolvents, leading to the
selective formation of the corresponding products (5a-5e). Next, we
assessed the applicability of this method with respect to the aldehyde
scope and the reaction outcome was not significantly affected by the
substitution pattern on the aldehyde (5f-5j). Additionally, it was
possible to expand the scope of the method with vinyl arenes
containing both electron-rich and electron-deficient functional groups
(5k-5p).
To gain some insights into the selectivity of the radical cascades, Scheme 2 Control experiments.
we investigated the frontier molecular orbitals (FMO) by conducting
Based on the above observations, a plausible mechanism for the
quantum chemical calculations based on density functional theory
current reactions is shown in Figure 2. Initially, the aldehyde reacts
(DFT), as depicted in Figure 1.20 The singly occupied molecular
with the NHC to yield neutral Breslow intermediate A. The enolate
orbital (SOMO) of the alkyl radical is located at −6.53 eV. While the
form B, generated after deprotonation, functions as a single-electron
highest occupied molecular orbital (HOMO) of alkene 4a is at −5.94
reductant, which undergoes a SET reduction of the Katritzky salt to
eV, the SOMO of the ketyl radical is found at −4.05 eV. The SOMO
furnish dihydropyridine radical C and ketyl radical D. Subsequently,
of the alkyl radical is closest and well matched with the occupied π
dihydropyridine radical C undergoes fragmentation to generate alkyl
orbital of the alkene, thus favoring the radical-olefin interaction. The
radical E and pyridine. The alkyl radical E ultimately engages in
SOMO energy level of the resultant benzyl radical is located at −4.91
radical-radical coupling with the carbonyl-carbon radical D to form
eV, which reacts with the ketyl radical to afford the three-component
the desired product and regenerates the NHC catalyst.
products, which is in good agreement with the experimental
observations.
Fig. 1 MO diagram of the alkyl radical interactions with alkene and ketyl
Fig. 2 Proposed reaction mechanism.
radical. Energies are given in eV.
4 | J. Name., 2012, 00, 1-3
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Chem. Rev., 2015, 115, 9307; (c) A. T. Biju and R. Breslow,
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2019.
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DOI: 10.1039/D0SC00225A
Conclusions
In summary, we have reported an NHC-catalyzed deaminative
radical−radical coupling strategy between readily available Katritzky
salts and aldehydes under mild and metal-free conditions. The
Katritzky salt behaves as a single-electron oxidant capable of
generating an alkyl radical enabled by the reduction of the enolate
form of a Breslow intermediate, offering a new opportunity for the
rapid modification of a series of amino compounds. Moreover, the
operational ease and broad functional group tolerance allow for the
modification of a series of peptide feedstocks. The broad utility of the
current versatile platform has been further magnified by the
application to the three-component dicarbofunctionalization of olefins
through a radical relay.
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18 CCDC 1964487 (1a), 1964495 (1g), 1964489 (3m), and
1964493 (3y) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures.
Acknowledgements
This research was supported financially by Institute for Basic
Science (IBS-R010-A2). We thank Dr. Dongwook Kim (IBS)
for XRD analysis
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